Salvador Castells

Effects of L-5-hydroxytryptophan on monoamine and amino acids turnover in the Lesch-Nyhan syndrome.

In a patient with the Lesch-Nyhan syndrome we found decreased spinal fluid 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of serotonin, and decreased homovanillic acid (HVA), the major metabolite of dopamine, indicating a decrease in monoamine metabolism. Administration of 5-hydroxytryptophan and carbidopa produced an increase in spinal fluid 5-HIAA, indicating that it might be possible to correct the serotonin deficiency in this syndrome, but there were no changes in the marked mental retardation and neurological deficits. Self-mutilation appeared to be suppressed by therapy but the effectiveness of the drugs decreased with time. There were also changes in the spinal fluid concentration of amino acids that might affect brain protein synthesis. These changes were corrected during administration of 5-hydroxytryptophan and carbidopa.

Growth retardation in fetal alcohol syndrome. Unresponsiveness to growth-promoting hormones.

The relationships between growth retardation and metabolic and hormonal parameters were studied in 7 children with fetal alcohol syndrome (FAS). Fasting blood concentrations of TSH, T4, T3, FSH and LH were normal. Plasma prolactin concentrations after chlorpromazine stimulation were normal. 3 children had abnormal oral glucose tolerance tests with increased plasma insulin response. Peak plasma growth hormone responses to insulin-induced hypoglycemia were elevated in 5 patients. Fasting bioassayable serum somatomedin activity, determined in 6 patients, was elevated in 3 patients and normal in 3 patients. Administration of hGH to 3 patients with FAS had little effect upon nitrogen retention and did not increase plasma insulin concentrations, although serum somatomedin activity sharply increased in 1 patient evaluated for somatomedin response. The data indicate that the growth defect in FAS is not due to deficiency of growth-promoting hormones, but rather to peripheral unresponsiveness.

Therapy of osteogenesis imperfecta with synthetic salmon calcitonin.

We evaluated the long-term use of synthetic salmon calcitonin in the management of osteogenesis imperfecta tarda and congenita. Forty-eight children, ranging in age from 6 months to 15 years, and two young adults, received synthetic salmon calcitonin 2 MRC units/kg three days a week and a daily oral calcium supplement of 230 to 345 mg. The annual fracture rate was decreased during calcitonin therapy as compared to the period preceding therapy. There was an increase in the ability of the patient to stand and move and in the subjective feeling of strength in the lower extremities during calcitonin therapy. There was also a significant improvement in radiographic bone density, as determined by the method of photodensitometry, in patients under 5 years of age. Long-term administration of synthetic salmon calcitonin may be beneficial to young children with osteogenesis imperfecta.

Familial thryoid disease: Lingual thyroid in two siblings and hypoplasia of a thyroid lobe in a third†

Summary Three siblings from one family had development abnormalities of the thyroid. Two of the three had sublingual thyroid, one presenting with hypothyroidism and the other with pressure symtoms. The third sibling had a congenital hypoplastic left lobe with normal thyroid activity.

Postprandial Hyperlipidemia after a Fat Loading Test in Minority Adolescents with Type 2 Diabetes Mellitus and Obesity

The continuing increase in the incidence of type 2 diabetes mellitus (DM2) and obesity in children and adolescents is attributable to excessive caloric intake. Abnormal lipid metabolism in the postprandial state leads to long exposure of the vasculature to hyperlipidemia. Most children and adolescents with DM2 are obese, and many have fasting hypertriglyceridemia. Clustering of hyperlipidemia, DM2 and obesity increases the risk for cardiovascular disease. We therefore studied lipids, insulin, C-peptide, and glucose in response to an oral fat load simulating the fat content of a high-fat, fast-food meal in 12 type 2 diabetic obese, 15 non-diabetic obese, and 12 non-diabetic non-obese (control) adolescents (aged 10-19 yr; 87% African-Americans). All three groups were age-, sex-, and sexual maturation-matched. Mean body mass indices were similar in the diabetes and obese groups (32.7 +/- 1.1 vs 35.8 +/- 1.6 kg/m2). All patients with DM2 had fasting C-peptide > 0.2 nmol/l (0.7 ng/ml) and negative diabetes-associated autoantibodies. Serum total cholesterol, triglyceride, high- and low-density lipoprotein cholesterol, insulin, C-peptide, and plasma glucose levels were measured at 0, 2, 4, and 6 h after the fat load. The area under the curve (AUC) was calculated by trapezoidal estimation. Triglyceride AUC was significantly greater in the diabetes group than in the other two groups (15.7 +/- 2.9 vs 9.2 +/- 0.7 and 7.5 +/- 0.7 mmol x h/l [1389 +/- 258 vs 819 +/- 60 and 663 +/- 62 mg x h/dl]; p < 0.02 and <0.004, respectively), as were insulin, C-peptide, and glucose AUCs. Incremental triglyceride response (delta triglyceride = peak - fasting) in the diabetes group was significantly higher than that in the control group (2.1 +/- 0.7 vs 0.8 +/- 0.1 mmol/l 189.7 +/- 58.4 vs 71.2 +/- 11.1 mg/dl]; p < 0.04). Insulin resistance was estimated using the homeostasis model assessment (HOMA), which was greater in the diabetes group than in the obese and control groups (14.4 +/- 2.8 vs 5.2 +/- 0.8 and 3.2 +/- 0.4; p < 0.001 and < 0.0001, respectively). The diabetes group was divided into subgroups of high and normal fasting triglycerides on the basis of triglyceride levels above and below the 95th percentile. The delta triglyceride in the subgroup with high fasting triglycerides was substantially greater than in the subgroup with normal fasting triglycerides (3.4 +/- 1.1 vs 0.8 +/- 0.2 mmol/l [305.2 +/- 96.8 vs 74.2 +/- 18.0 mg/dl]; p < 0.001). Total cholesterol and triglyceride AUCs were much greater in the high vs normal fasting triglycerides subgroup (33.0 +/- 2.9 vs 24.2 +/- 1.9 and 23.6 +/- 3.5 vs 7.8 +/- 0.6 mmol x h/l [1274 +/- 113 vs 934 +/- 72 and 2085 +/- 309 vs 692 +/- 49 mg x h/dl]; p < 0.02 and <0.0001, respectively), as were insulin and C-peptide AUCs. HOMA was greater in the high vs normal fasting triglycerides subgroup (20.8 +/- 4.0 vs 8.0 +/- 1.6; p < 0.0001). In addition to elevated plasma glucose levels, there were no significant differences in either insulin or lipid parameters among the diabetes subgroup with normal fasting triglycerides, the obese group, and controls. Our data suggest that postprandial hyperlipidemia in response to a fat loading test is present in adolescents with DM2 who already have fasting hypertriglyceridemia. The degree of insulin resistance as an underlying abnormality--not DM per se--determines the degree of postprandial lipemia.

Familial moniliasis, defective delayed hypersensitivity, and adrenocorticotropic hormone deficiency

Five siblings, 2 normal and 3 with moniliasis, cutaneous anergy, and limited pituitary adrenocorticotropin reserve, were studied. The affected siblings failed to manifest delayed hypersensitivity. Endocrine studies showed that the affected siblings had almost no increase in urinary excretion of 17-ketogenic steroids after adrenocorticotropin infusion, and a significantly lower increase in 17-ketogenic steroid excretion during a metyrapone test as compared to control subjects. One sibling had hypoparathyroidism.

Direct sequencing of PCR products derived from cDNAs for the proα1 and proα2 chains of type I procollagen as a screening method to detect mutations in patients with osteogenesis imperfecta

More than 150 mutations in the genes for type I procollagen have been found in unrelated patients with osteogenesis imperfecta (OI), but mutations have been difficult to define in many patients with the mildest forms of the disease. Here, we have used robotically automated sequencing of the cDNAs for type I procollagen to screen for mutations in 12 patients suspected of having nonlethal OI (types I, III, and IV). Single base mutations that changed codons for obligate glycine residues were found in seven of the patients. Altogether, we analyzed 4,379 bp of sequences of both alleles of the proα1(I) collagen (8,758 bp of allelic sequences) and 4,200 bp of sequences of both alleles of the proα2(I) collagen (8,400 bp of allelic) from each patient.

Effects of porcine calcitonin in osteogenesis imperfecta tarda.

The effect of the administration of porcine calcitonin to two children with osteogenesis imperfecta tarda was evaluated by means of calcium and phosphorus balance studies, urinary hydroxyproline excretion, tubular reabsorption of phosphorus, and phosphate clearance before and after administration of parathyroid extract. The balance studies indicated that calcitonin was effective in causing retention of calcium and phosphorus and decrease in hydroxyproline excretion. These improvements suggest that calcitonin may be of therapeutic value in osteogenesis imperfecta by decreasing bone resorption.

Plasminogen Activator Inhibitor-1 and Tissue-Plasminogen Activator in Minority Adolescents with Type 2 Diabetes and Obesity

Increased plasminogen activator inhibitor-1 (PAI-1) and decreased tissue-plasminogen activator (t-PA) activities lead to impaired fibrinolysis, which is critical for cardiovascular disease. We studied these hemostatic factors at fasting state and after an oral fat load in 12 type 2 diabetic and 17 nondiabetic obese adolescents, matched for age, sex, body mass index, and sexual maturation. Plasma PAI-1, t-PA, and glucose as well as serum C-peptide, insulin, total cholesterol, triglyceride, and HDL and LDL cholesterol levels were measured at 0, 2, 4, and 6 h after the fat load. Metabolic responses were expressed as the area under the curve (AUC). PAI-1 activities were significantly greater in patients than in control subjects [fasting, 23.4 ± 2.6 versus 12.9 ± 2.0 U/mL (p < 0.004); AUC, 101.7 ± 12.1 versus 57.6 ± 6.5 U · h−1 · mL−1 (p < 0.003)]. Fasting t-PA activities were significantly lower in the patients than in the control subjects (0.8 ± 0.3 versus 6.5 ± 2.7 U/mL; p < 0.001). Triglyceride was the only lipid parameter that was significantly different in the patients than in the control subjects [fasting, 1.5 ± 0.2 versus 0.9 ± 0.1 mM (p < 0.05); AUC, 15.7 ± 2.9 versus 7.9 ± 0.6 mmol · h−1 · L−1 (p < 0.02)]. The PAI-1 activities decreased significantly during the loading tests (p < 0.0001), whereas the t-PA activities did not change. Insulin resistance estimated by the homeostasis model assessment was greater in the patients than in the control subjects (14.4 ± 2.8 versus 4.6 ± 0.7; p < 0.0001). We conclude that elevated PAI-1 and diminished t-PA activities, suggestive of suppressed fibrinolysis, are present in our adolescents with type 2 diabetes; adding another risk factor for cardiovascular disease and acute high fat load does not further negatively affect this suppressed fibrinolysis.

Hypocalcemia in Children: Pathogenesis and Management

Hypocalcemia can be devastating if unrecognized. Neuromuscular dysfunction occurs in severe cases. A review and an update on the topic may assist general pediatricians. The authors provide a general overview of pathogenesis and management of hypocalcemia in children.